Research Challenge Area: (13) Smart Biomaterials - Theranostics Specific Challenge Topic: 13-ES-101* Methods to evaluate the health and safety of nanomaterials. Project Title: Imaging nanoparticle interactions with living systems The lack of an accurate and rapid method for measuring nanoparticle interactions with living systems presents a huge barrier to their effective use and to the development of safer nanotechnologies. We propose to advance molecular imaging with PET as an experimental platform upon which we can begin to identify structural predictors of nanoparticle fate. We will first optimize several radiolabeling methods to develop short-lived radioactive nanoparticles with physico-chemical properties that are identical to their unlabeled counterparts, that are stable in vivo and whose radiosynthesis is sufficiently flexible to apply to a diverse set of particles. Next, we will use these probes to test two specific hypotheses: first, that the concentration and size of several different engineered nanomaterials affects their uptake and distribution in intact, living systems. For this, we will use carbon-11 labeled particles (20.4 min half-life) and perform serial studies in the same experimental setting using different concentrations of cold nanoparticles on animals (administered intra- venously). This will give important information about the rate and saturability of nanomaterial dispersion as a function of size in vivo. Second, we will test the hypothesis that the distribution of nano-materials predicts which organs and tissues will show an inflammatory response. For this, we will use carbon-11 labeled nano- particles and perform serial PET scans, only this time we will monitor macrophage accumulation with [11C]- PK11195 or neutrophil activation with FDG at several time points up to three months after the first nano- particle scan. Those tissues which show a high accumulation of nanomaterials will be prepared for light and electron microscopy to identify (a) nanoparticle cellular and intracellular localization, (b) whether the nano- particle has been altered (degraded) and (c) any evidence of cell/tissue damage associated with nanoparticle accumulation (histochemistry and ultramicroscopy). Importantly, biological, physical and chemical characterization of candidate nanomaterials will occur at multiple time points through both sets of experiments. PET derived kinetic models will allow us to describe and predict the rate at which candidate nanomaterials enter and exit plasma and tissue compartments of diverse living systems, and how this is altered by systematic manipulations of radionuclide attachment, size and core material. The application of PET to evaluate the health and safety of nanomaterials will offer a deep and broad understanding of nanoparticle behavior, revealing the pathways nanomaterials take in living systems and identifying some of the acute and long-term effects of nanoparticle exposure with outcomes that are directly relevant to human health. These studies will allow us to establish a quantitative framework for identifying the biological effects of nanoparticle exposure. We will develop new imaging probes (Aim 1) and use in vivo approaches to capture organ distribution (Aim 2) and physiologic tissue responses (Aim 3) over time. This data will be substantiated at a light and electron microscopic level to ascertain nanoparticle fate (Aim 2) and the functional integrity of targeted cells (Aim 3). We will develop the tools necessary to apply molecular imaging with Positron Emission Tomography (PET) to evaluate the health and safety of nanomaterials. This will offer a deep and broad understanding of nanoparticle behavior, revealing the pathways nanomaterials take in living systems and identifying some of the acute and long-term effects of nanoparticle exposure with outcomes that are directly relevant to human and environmental health. PUBLIC HEALTH RELEVANCE: We will develop the tools necessary to apply molecular imaging with Positron Emission Tomography (PET) to evaluate the health and safety of nanomaterials. This will offer a deep and broad understanding of nanoparticle behavior, revealing the pathways nanomaterials take in living systems and identifying some of the acute and long-term effects of nanoparticle exposure with outcomes that are directly relevant to human and environmental health.